Locomotor sensitization to intermittent ketamine administration is associated with nucleus accumbens plasticity in male and female rats

- Repeated, intermittent, low-dose ketamine induces locomotor sensitization at a lower dose in female rats than males.
- Ketamine sensitization was associated with increased dendritic spine density in the nucleus accumbens of males and females.
- Ketamine sensitization was associated with increased protein expression in the nucleus accumbens of male and female rats.

Clinical evidence suggests superior antidepressant response over time with a repeated, intermittent ketamine treatment regimen as compared to a single infusion. However, the club drug ketamine is commonly abused. Therefore, the abuse potential of repeated ketamine injections at low doses needs to be investigated. In this study, we investigated the abuse potential of repeated exposure to either 0, 2.5, or 5 mg/kg ketamine administered once weekly for seven weeks. Locomotor activity and conditioned place preference (CPP) were assayed to evaluate behavioral sensitization to the locomotor activating effects of ketamine and its rewarding properties, respectively. Our results show that while neither males nor females developed CPP, males treated with 5 mg/kg and females treated with either 2.5 or 5 mg/kg ketamine behaviorally sensitized. Furthermore, dendritic spine density was increased in the NAc of both males and females administered 5 mg/kg ketamine, an effect specific to the NAc shell (NAcSh) in males but to both the NAc core (NAcC) and NAcSh in females. Additionally, males administered 5 mg/kg ketamine displayed increased protein expression of ΔfosB, calcium calmodulin kinase II alpha (CaMKIIα), and brain-derived neurotrophic factor (BDNF), an effect not observed in females administered either dose of ketamine. However, males and females administered 5 mg/kg ketamine displayed increased protein expression of AMPA receptors (GluA1). Taken together, low-dose ketamine, when administered intermittently, induces behavioral sensitization at a lower dose in females than males, accompanied by an increase in spine density in the NAc and protein expression changes in pathways commonly implicated in addiction.